EP0312086A2 - Polysulfuric esters of amides of bis-aldonic acids and their derivatives, a method for their preparation and a drug - Google Patents

Abstract

The aldonic acids on which the esters are based can be linked glycosidically in position 3, 4 or 6 to a galactopyranosyl, mannopyranosyl, glucopyranosyl or oligopyranosyl radical. The compounds have therapeutic activity.

Description

worin entweder

• sämtliche Reste R¹, R² und R³ unabhängig voneinander für X stehen, oder
• zwei der Reste R¹, R² und R³ für X, und der dritte für einen Rest der Formeln II - VII stehen,
  
  
  
  
  
  
• X in den Formeln I bis VII gleichzeitig oder unabhängig voneinander ein Wasserstoffatom oder die Gruppe
• -SO₃H bedeutet, wobei mindestens ein X für die Gruppe -SO₃H steht,
• m für 0,1,2,3,4,5 oder 6 steht,
• A in Formel I für einen gegebenenfalls durch einen oder mehrere Reste -CO₂R⁵ substituierten geradkettigen oder verzweigten, gesättigten Alkylenrest mit 2 bis 22 Kohlenstoffatomen steht, und dieser Alkylenrest gegebenenfalls durch bis zu 5 -O-, -S-, -S-S-, -S(O)n-, O
• - 8 -NH- oder/und -NR⁶-Gruppen oder Cycloalkylen- oder Arylenreste unterbrochen ist, oder A für eine einfache Bindung oder den Rest
  
  steht,
• n 1 oder 2 ist,
• R⁴, R⁵ und R⁶ gleichzeitig oder unabhängig voneinander ein Wasserstoffatom oder einen C₁-C₆-Alkylrest bedeuten,
• sowie deren Salze mit anorganischen oder organischen Basen.

The invention relates to polysulfuric acid esters of bis-aldonic acid amides and their derivatives of the general formula I,

wherein either

• all radicals R ¹ , R ² and R ³ independently of one another represent X, or
• two of the radicals R ¹ , R ² and R ^{3 represent} X, and the third represent a radical of the formulas II-VII,
  
  
  
  
  
  
• X in the formulas I to VII simultaneously or independently of one another is a hydrogen atom or the group
• Means -SO ₃ H, where at least one X represents the group -SO ₃ H,
• m stands for 0,1,2,3,4,5 or 6,
• A in formula I represents a straight-chain or branched, saturated alkylene radical having 2 to 22 carbon atoms optionally substituted by one or more -CO ₂ R ⁵ radicals, and this alkylene radical optionally by up to 5 -O-, -S-, -SS- , -S (O) n-, O
• - 8 -NH or / and -NR ⁶ groups or cycloalkylene or arylene radicals is interrupted, or A for a simple bond or the rest
  
  stands,
• n is 1 or 2,
• R ⁴ , R ⁵ and R ⁶ mean simultaneously or independently of one another a hydrogen atom or a C ₁ -C ₆ alkyl radical,
• and their salts with inorganic or organic bases.

These compounds according to the invention are active ingredients with valuable pharmacological properties, as will be explained further below.

The following explanations apply to the various substituents or radicals mentioned in connection with the present invention and description (in the various formulas given):

worin R', R² und R³ die angegebene Bedeutung besitzen. Diese Aldonsäuren können in der D-Form, der L-Form oder in Form ihrer Razemate, bevorzugt in ihrer in der Natur überwiegenden Form, vorliegen.The aldonic acids on which the present poly sulfuric acid esters are based have the general formula VIII

wherein R ', R ² and R ^{3 have} the meaning given. These aldonic acids can be in the D form, the L form or in the form of their racemates, preferably in their form which is predominant in nature.

Examples of these aldonic acids include the hexonic acids allonic, altronic, galactonic, gluconic, gulonic, idonic, mannonic and talonic, preferably galactonic, gluconic, gulonic and mannonic. Further examples are derivatives of these hexonic acids which are glycosidically linked to a radical R ³ or R ² or R 'of the formulas II to VII in which X represents hydrogen on the oxygen atoms in the 3-, 4- or 6-position. The bond here can be α- or β-glycosidic. The residues II to V are galactopyranosyl and mannopyranosyl residues. The residues VI and VII are glucopyranosyl residues (in the event that m = 0) and a (1-4) or β (1 → 4) -linked oligoglucopyranosyl residues (if m = 1 to 6). In formulas VI and VII, the index m is preferably 0 or 1. The saccharide units linked to the aldonic acid are normally in the D form. Examples of hexonic acids of the general formula VIII which are substituted by radicals of the formulas II to VII are glucopyranosylgluconic acids, glucopyranosylmannonic acids, glucopyranosylgalactonic acids, galactopyranosylgluconic acids, mannopyranosylgluconic acids, mannopyranosylgluconic acids and oligogluconic acids. Lactobionic acid (4-O-β-D-galactopyranosylgluconic acid), gentiobionic acid, melibionic acid (6-OaD-galactopyranosylgluconic acid), mannobionic acid, cellobionic acid (4-0-β-D-glucopyranosylgluconic acid) and maltobionic acid (4-O-glucopyranosylgluconic acid) are preferred. as well as maltotrionic acid and cellotrionic acid.

Examples of salt-forming bases are trialkylamines with 1 to 6 carbon atoms in the alkyl part, such as trimethylamine, triethylamine, tripropylamine, tributylamine, tripentylamine and trihexylamine. Trimethylamine, triethylamine and tributylamine are preferred.

Examples of physiologically acceptable inorganic and organic salts are the ammonium, lithium, sodium, potassium, magnesium, calcium, aluminum salts and the salts with ethanolamine, triethanolamine, morpholine, pyridine and piperidine. The sodium, potassium, calcium, aluminum and ethanolamine salts are preferred.

Examples of straight-chain or branched, saturated alkylene radicals with 2 to 22 carbon atoms which represent group A are ethylene, tri, tetra, penta-, hexa-, hepta-, octa-, nona-, deca-, undeca-, Dodeca-, tetradeca-, hexadeca-, octadeca-, icosa- and docosamethylene as well as methylethylene, methylpropylene, methylbutylene, methylpentylene and dimethylethylene. Ethylene, tri, tetra, hexa, nona, dodeca and docosamethylene as well as methyl ethylene and methyl pentylene are preferred.

Examples of arylene radicals through which the alkylene group A can be interrupted are phenylene, naphthylene, anthrylene, phenanthrylene and fluorenylene. Ortho-, meta- and para-phenylene radicals are preferred here.

Examples of cycloalkylene radicals through which the alkylene radical of group A can be interrupted are cyclopentylene, cyclohexylene, cycloheptylene and cyclooctylene, 1,3- and 1,4-cyclohexylene being preferred here.

The straight-chain or branched, saturated alkylene radical of group A preferably has 2 to 12 carbon atoms. If the straight-chain or branched, saturated alkylene radical of group A is interrupted by one of the radicals or groups mentioned, it is preferably 1 or 2 such radicals or groups.

Specific examples of the definition of alkylene radicals which represent group A are the groups derived from the following α, ω-diamines:

Enantiomere des Lysins (R⁵ = H) und seiner Ester (R⁵ = C₁-C₆-Alkyl)

Enantiomers of lysine (R ⁵ = H) and its esters (R ⁵ = C ₁ -C ₆ alkyl)

with S atoms:

• R ^S O ₂ C-HC (NH ₂ ) -CH ₂ S-CH ₂ - (NH ₂ ) CH-CO ₂ R ⁵
• Lanthionine diastereomers (R ⁵ = H)
• and esters (R ^S = C ₁ -C ₆ alkyl)
• R ⁵ O ₂ C-HC (NH ₂ ) - (CH ₂ ) _X SS- (CH ₂ ) _x (NH ₂ ) CH-CO ₂ R ⁵
• Diastereomers of cystine (x = 1, R ⁵ = H)
• and esters (R ⁵ = C ₁ -C ₆ alkyl)
• Diastereomers of homocystine (x = 2, R ⁵ = H)
• and esters (R ^S = C ₁ -C ₆ alkyl)
• H0 ₂ C-CH (NH ₂ ) - (CH ₂ ) ₂ -S-CH ₂ -CH (NH ₂ ) -C0 ₂ H
• Diastereomers of cystathionine
  

Group A can preferably represent the following radicals:

Examples of C ₁ -C ₆ -alkyl radicals from the groups R ⁴ , R ⁵ and R ⁶ are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, tert-butyl, neopentyl , with methyl, ethyl, n-propyl, isopropyl, tert-butyl and n-butyl being preferred.

worin R¹, R², R³, R⁴ und A die angegebenen Bedeutungen haben, wobei jedoch X in den Formeln II bis VII für Wasserstoff steht, in einem aprotischen Lösungsmittel mit einem Sulfatierungsmittel umsetzt und die so erhaltenen Produkte mit einer anorganischen oder organischen Base in die entsprechenden Salze überführt. Man erhält die Verbindungen der allgemeinen Formel IX in Analogie zu liter aturbekannten Verfahren (z.B.: F. Scholnick, P.E. Pfeffer, J. Dairy Sci. 63 (3), 471 (1980); W.N. Emmerling, B. Pfannemüller, Starch 33 (6), 202 (1981)). Zur Herstellung der Bis-aldonsäureamide der allgemeinen Formel IX läßt man Lactone der Aldonsäuren der allgemeinen Formel VIII mit einer Diaminoverbindung R⁴HN-A-NHR⁴ in einem Lösungsmittel reagieren. Die Lactone können dabei sowohl in der 1,4-Lactonform der allgemeinen Formel X als auch in der 1,5-Lactonform der allgemeinen Formel XI eingesetzt werden.

The invention also relates to a process for the preparation of polysulfuric esters of bis-aldonic acid amides of the general formula I, which is characterized in that bis-aldonic acid amides of the general formula IX

wherein R ¹ , R ² , R ³ , R ⁴ and A have the meanings given, but X in the formulas II to VII is hydrogen, reacted in an aprotic solvent with a sulfating agent and the products thus obtained with an inorganic or organic Base converted into the corresponding salts. The compounds of the general formula IX are obtained analogously to processes known from the literature (for example: F. Scholnick, PE Pfeffer, J. Dairy Sci. 63 (3), 471 (1980); WN Emmerling, B. Pfannemüller, Starch 33 (6 ), 202 (1981)). To prepare the bis-aldonic acid amides of the general formula IX, lactones are allowed to Aldonic acids of the general formula VIII react with a diamino compound R ⁴ HN-A-NHR ⁴ in a solvent. The lactones can be used both in the 1,4-lactone form of the general formula X and in the 1,5-lactone form of the general formula XI.

The compounds of the general formulas X and XI are obtained by elimination of water from the aldonic acids VIII. The aldonic acids can be obtained by processes known from the literature (for example WN Emmerling, B. Pfannemüller, Starch 33 (6), 202 (1981); R. Schaffer, HS Isbell, J. Am. Chem. Soc. 81, 2178 (1959), HW Diehl et al., Carbohydrate Research 38, 364 (1974)) can be obtained from the corresponding aldoses by electrochemical or hypohalite oxidation. For the preparation of the bis-aldonic acid amides of the general formula IX, 2 moles of aldonic acid lactone are used per mole of diamino compound. Suitable solvents for the reaction are methanol, ethanol, ethylene glycol, dimethyl sulfoxide, dimethylformamide or N-methylpyrrolidone. Dimethylformamide is preferred. The reaction times range from several hours to days, preferably between 5 and 8 hours. The reaction temperatures are between room temperature and the boiling temperatures of the respective solvents, preferably between 40 C and 80 C. The aldonic acid amides either crystallize out of the reaction solution or can be precipitated by adding an organic solvent. Methanol, ethanol, isopropanol or acetone, preferably isopropanol, are suitable for this.

The bis-aldonic acid amides or general formula IX are the subject of German patent application P ....... by the same applicant on the same filing date (Case BAA, title "Bis-aldonic acid amides and processes for their preparation"), the disclosure of which is incorporated herein by reference should be.

For the preparation of the present compounds of general formula 1, the bis-aldonic acid amides of formula IX are dissolved or suspended in an aprotic solvent. Pyridine, dimethylformamide, dimethylacetamide, N-methylpyrrolidone etc. are suitable; dimethylformamide is preferred.

The mixture is heated to temperatures between 20 ° C. and 100 ° C., preferably between 30 ° C. and 70 ° C., and a sulfating agent is added. Examples of these are chlorosulfonic acid, sulfur trioxide, oleum, ether or amine-sulfur trioxide complexes. The sulfur trioxide complexes with trimethylamine, triethylamine and pyridine are preferably used.

In order to obtain polysulfuric acid esters of bis-aldonic acid amides of the general formula I, in which each X represents the group -SO ₃ H, 1 to 2 equivalents of sulfating agent, preferably 1.4-1.7 equivalents, are used for each esterifiable hydroxyl group. Compounds in which not every X represents the group -SO ₃ H are obtained if the sulfating agents are used in a deficit. Depending on how high the sulfur content of the product should be, the amount of sulfating agent is chosen. Amounts between 0.5 and 1 equivalent of sulfating agent per esterifiable hydroxyl group are preferred. The reaction mixture is stirred for 1 to 24 h at temperatures between 20 ° C. and 100 ° C. From the polysulfate compounds of the general formula I obtained in this way, in which X represents —SO ₃ H, which is also the salt of the amine of the amine-sulfur trioxide complex used can be present, the corresponding salts of inorganic bases are obtained by adding these bases or their inorganic salts. The hydroxides and acetates of the alkali and alkaline earth metals are preferably used here. Salts of physiologically harmless organic bases are obtained either by using a sulfur trioxide complex of these bases in the sulfation reaction or by treating the alkaline earth metal or alkali salts with a cation exchanger in the acidic form and subsequent neutralization of the acidic sulfuric acid half-esters with the organic base. The compounds according to the invention are generally isolated by precipitation from the reaction solutions or from aqueous solutions with organic solvents. Suitable organic solvents are methanol, ethanol, isopropanol or acetone, preferably methanol.

The compounds can be purified by reprecipitation from aqueous solutions with the abovementioned solvents and by treatment with activated carbon or hydrogen peroxide. In general, the products obtained in this way are mixtures with a more or less high content of compounds, all of whose hydroxyl groups are esterified with sulfate residues and of compounds, whose hydroxyl groups are only partially sulfated, depending on the amount of sulfating agent used. The mixtures obtained can optionally be separated into products with a uniform content of sulfate residues by various separation processes. The separation can be carried out according to different physical separation processes, such as fractional precipitation, gel, ion exchange or affinity chromatography, HPLC or electrophoretic processes. Fractional precipitation is preferred. For example, an aqueous solution of the product mixture is prepared and one to four times the amount of an organic solvent is added. Water-miscible solvents such as methanol, ethanol, isopropanol, acetone or tetrahydrofuran are suitable; methanol is preferred. The precipitate thus obtained is allowed to settle. In general, the compounds with a higher sulfate content are now enriched in the precipitation, those with a lower sulfate content in the supernatant solution. Repeated fractional precipitation of the precipitates or supernatants gives compounds with a defined number of sulfate groups.

In a preferred embodiment of the process according to the invention, the compounds of the formula I are produced from the aldonic acids of the formula VIII without isolation of the necessary intermediates.

This is based on commercial or known literature methods (e.g. WN Emmerling, B. Pfannemüller, Starch 33 (6), 202 (1981); R. Schaffer, HS Isbell, J. Am. Chem. Soc. 81, 2178 ( 1959), HW Diehl et al., Carbohydrate Research 38, 364 (1974)) synthesized alkali or alkaline earth salts of aldonic acids VIII by means of a cation exchanger and largely concentrated an aqueous solution of free aldonic acids VIII. The lactones corresponding to aldonic acids VIII are now generated in situ by elimination of water. For this purpose, the residue, which is generally a water-containing mixture of aldonic acid and lactone, is dissolved in a high-boiling solvent. Examples of high-boiling solvents are dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, dimethoxymethyl ether etc., dimethylformamide is preferred. Now a second, low-boiling solvent is added, which can form an azeotrope with water. Suitable solvents are, for example, n-pentane, n-hexane, cyclohexane, benzene etc., n-hexane is preferred. At the water separator, water is then split off quantitatively from the aldonic acids. Then the low-boiling entrainer is distilled off and the lactone present in the remaining high-boiling solvent is reacted with the diamino compound without isolating the same. The reaction temperatures are between 20 ° C and 120 ° C, preferably between 50 ° C and 80 ° C. Stirring is carried out over a period of 3 to 24 hours, preferably 3 to 8 hours. Without isolating the bis-aldonic acid amide formed, it is reacted with a sulfating agent in the same reaction vessel. Reaction conditions as well as isolation and purification of the products are described in the aforementioned process.

The compounds of general formula I are pharmacologically valuable substances. They have anti-thrombotic and anti-inflammatory properties. The compounds according to the invention are therefore suitable for the treatment of diseases of the rheumatic type and for the prophylaxis and therapy of venous and arterial thromboses. The invention therefore also relates to a medicament for use in humans and animals. Use in humans is preferred.

The antithrombotic activity of the compounds according to the invention is particularly surprising.

To date, heparin has been used primarily for thrombosis prophylaxis. Heparin is a mucopolysaccharide isolated from animal tissue, particularly pig intestine (Thomas, DP (1981) in Clinics in Haematology, Vol. 10, pp. 443-458, Saunders Comp. Ltd., 1981). In addition to heparin, other naturally occurring mucopolysaccharides such as dermatan sulfate or heparan sulfate also have antithrombotic properties (Rosenberg, RD, Rosenberg, JS (1984), J. Clin. Invest. 74, 1-6; Sie, P., Ofosu, F., Fernandez, F., Buchanan, MR, Petitou M., Boneu, B. (1986) Br. J. Haematol. 64, 707-714). A semisynthetic chondroitin polysulfate is also known, for example from DE-PS 31 18 588, which has, among other things, antithrombotic properties. However, only heparin is used therapeutically. Recently, some low molecular weight heparins have been developed for clinical use. These are substances which are obtained from heparin by various chemical or enzymatic depolymerization processes (Thomas, DP, Merton, RE (1982) Thrombos. Res. 28, 343-350; Walenga, JM, Fareed, J., Petitou, M., Samana, M., Lormeau, JC, Choay, J. (1986) Thrombos. Res. 43, 243-248; Koller, M., Schoh, U., Buchmann, P. Largiader, F., von Felten, A., Frick, PG (1986) Thrombos. Haemostas. 56, 243-246).

A disadvantage of the heparins and low molecular weight heparins is that they are of natural origin (e.g. from animals). Small amounts of antigen are therefore present in animal tissue and can lead to anaphylactoid reactions such as platelet drop, thrombosis and embolism. While these side effects are relatively rare, they are serious and difficult to manage clinically.

In contrast, the compounds of the invention are fully synthetic and therefore free from animal antigen.

Another much more common complication of thromboprophylaxis with heparin and low molecular weight heparin is the appearance of bleeding. Substances that cause less bleeding with the same antithrombotic effect can therefore represent a significant therapeutic advance.

Several pharmacological tests were used to test the compounds according to the invention for antithrombotic activity and anti-inflammatory activity.

1. Accelerate fibrinolysis

The development of a clinically manifest (larger) thrombus can be prevented in various ways. Firstly, the factors involved in the formation of the primary thrombus, such as platelet aggregation or the blood coagulation system, can be eliminated. On the other hand, increasing the body's fibrinolysis can accelerate the dissolution of the primary thrombus. Enhancing the body's own fibrinolysis can also serve to dissolve thrombi that are already clinically manifest. The fibrinolytic effect of a substance is therefore of great importance in the prophylaxis and therapy of thromboses. The fibrinolytic effect of the substances according to the invention was determined in the test below. The test is a slight modification of a method known from the literature for determining the fibrinolytic activity (Kluft, C. (1979) Thromb. Haemostas. 41, 365 - 383).

Fibrinolysis test

• Petrischalen, 0 9 cm, wurden auf 40 °C vorgewärmt. Unter Schwenken der Schale wurden 3 ml einer 2 % Lösung von Fibrinogen (Behringwerke, Marburg) in Wasser, 1 ml einer Plasminogenlösung, 2 CTA/ml (Behringwerke, Marburg), 3 ml einer 1 % Agaroselösung (Serva, Heidelberg) in 50 mM TRIS/HCI, pH 7,8 und 1 ml einer Lösung von 15 U/ml Thrombin (Behringwerke, Marburg) in Wasser einpipettiert. Nach Abkühlen der Platte wurden Löcher von 5 mm Durchmesser ausgestanzt.
• 0,1 ml Plasma (Humanes Standardplasma, Behringwerke, Marburg), 0,8 ml Wasser und 0,1 mi-Lösung der Testsubstanz in verschiedenen Konzentrationen wurden 10 Minuten bei 37 °C inkubiert. Nach Zusatz von 0,9 ml 0,025 % Essigsäure wurde 5 Minuten bei 4 °C inkubiert und anschließend bei 2000 g 5 Minuten zentrifugiert. Der Niederschlag wurde in 0,1 ml Puffer (20 mM TRIS/HCI, 100 mM NaCI, 2,7 mM EDTA, pH 7,8) aufgenommen.

Fibrinolysis was determined using plasminogen-containing fibrin plates.

• Petri dishes, 0 9 cm, were preheated to 40 ° C. While swirling the dish, 3 ml of a 2% solution of fibrinogen (Behringwerke, Marburg) in water, 1 ml of a plasminogen solution, 2 CTA / ml (Behringwerke, Marburg), 3 ml of a 1% agarose solution (Serva, Heidelberg) in 50 mM TRIS / HCl, pH 7.8 and 1 ml of a solution of 15 U / ml thrombin (Behringwerke, Marburg) are pipetted into water. After the plate had cooled, holes of 5 mm in diameter were punched out.
• 0.1 ml plasma (human standard plasma, Behringwerke, Marburg), 0.8 ml water and 0.1 ml solution of the test substance in different concentrations were incubated at 37 ° C. for 10 minutes. After the addition of 0.9 ml of 0.025% acetic acid, the mixture was incubated at 4 ° C. for 5 minutes and then centrifuged at 2000 g for 5 minutes. The precipitate was taken up in 0.1 ml buffer (20 mM TRIS / HCl, 100 mM NaCl, 2.7 mM EDTA, pH 7.8).

0.02 ml of this solution and 0.005 ml of 14.3 mM flufenamic acid solution (Sigma, Taufkirchen) in buffer are pipetted into the application holes of the fibrin plates. After 24 hours at 37 C the lysis yards were planimetrized. The area of the lysis yards minus the lysis area without added substance served as a measure of the fibrinolysis-increasing activity.

Result: The result is shown in the table below.

2. Inhibition of blood clotting

The inhibition of blood coagulation can be measured in a simple manner using the activated partial thromboplastin time aPTT. It provides information about the general inhibition of the activated coagulation system. In order to reduce the incidence of bleeding, the least possible inhibition of blood clotting is desirable here.

Coagulation test, aPTT

0.1 ml of plasma and 0.1 ml of Pathromtino (Behringwerke, Marburg) are incubated for 2 minutes at 37 ° C. and mixed with 0.1 ml of 25 mM CaC1 ₂ solution. The clotting time is measured in a Schnitger & Gross coagulometer. The mean is formed from 5 individual determinations per concentration. A heparin from Pharmindustrie with 175 U / mg is used as standard.

The extension of the clotting time is converted into heparin units via a calibration curve. Since the calibration curves are not parallel, the extension of the clotting time to 150% of the initial value is chosen as the reference point.

Result: The following table shows the heparin units of compounds according to the invention.

3. Influencing the bleeding time

Rats were cut an approximately 2 mm long piece of the tail. The time to stop bleeding was measured. The animals were given the test substance in various concentrations or physiological saline (control) 5 minutes before the bleeding started. Groups of 20 animals were treated. The prolongation of the bleeding time compared to the control was expressed as a percentage.

4. Anti-inflammatory effect

In inflammatory processes, large amounts of reactive oxygen species, including superoxide radicals and hydroxyl radicals, are released from the phagocytes (polymorphonuclear leukocytes and macrophages). These radicals are involved in tissue destruction. Substances that inhibit the formation of radicals in leukocytes are therefore of great therapeutic interest in combating inflammation (Flohe, L., Giertz, H., Beckmann, R. (1985) in The Pharmacology of inflammation, Vol 5 (Bonta, I . et al. eds.) pp. 255-281, Elsevier, Amsterdam-New York.

The radical formation of leukocytes can be measured by measuring the luminol-enhanced chemiluminescence in whole blood (Peter, M. et al. (1985) in Chi. Forum 85 (Stelzner, F., eds), pp. 81-84, Springer Verlag, Berlin).

Anti-inflammatory test

Test substances are dissolved in PBS and dilution series prepared in PBS. 600 μl PBS, 100 μl solution of the test substance, 100 μl zymosan suspension (100 mg / ml) and 100 μl rabbit citrate blood are pipetted into cuvettes which match a 1251 luminometer from LKB. The measurement is started by adding 100 µl 10- ³ M luminol solution. Chemiluminescence is measured every 5 minutes in each batch for 90 minutes. The maximum chemiluminescence is determined. An approach without test substance serves as a reference value. An approach without the addition of zymosan serves as a blank. Three independent determinations are carried out for each substance. The remaining chemiluminescence is calculated using the formula:

A semilogarithmic plot of residual chemiluminescence over log concentration results in concentrations of 50% CL inhibition (ICso values).

Result:

The inhibition of the luminol-enhanced CL by compounds according to the invention is shown in the table below.

The present invention also relates to pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more active compounds according to the invention or which consist of one or more active compounds according to the invention.

Non-toxic, inert pharmaceutically suitable carriers are to be understood as solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.

Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders, sprays and aerosols may be mentioned as preferred pharmaceutical preparations.

Tablets, dragées, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as a) fillers and extenders, for example starches, lactose, cane sugar, glucose, mannitol and silica, b) binders, for example carboxymethyl cellulose, Alginates, gelatin, polyvinylpyrrolidone, c) humectants, for example glycerol, d) disintegrants, for example agar-agar, calcium carbonate and sodium bicarbonate, e) solution retarders, for example paraffin and f) absorption accelerators, g) wetting agents, for example cetyl alcohol, glycerol monostearate, h) adsorbents, for example kaolin and bentonite and i) lubricants, for example talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under a) to i).

The tablets, dragees, capsules, pills and granules can be provided with the customary coatings, optionally containing opalizing agents, for example sugar, coating varnishes, and can also be composed such that they contain the active ingredient (s) only or preferably in a certain part of the intestinal tract, if appropriate release with a delay, whereby polymer substances and waxes can be used as embedding materials.

The active ingredient (s) can optionally also be in microencapsulated form with one or more of the excipients just specified.

In addition to the active ingredient or ingredients, suppositories can contain the usual water-soluble or water-insoluble carriers, for example polyethylene glycols, fats, for example cocoa fat and higher esters (for example CH alcohol with C, s-fatty acid or mixtures of these substances).

In addition to the active ingredient (s), ointments, pastes, creams and gels can contain the usual excipients, for example animal and vegetable fats and their derivatives, waxes, paraffins, emulsifiers, starch, tragacanth, cellulose derivatives, polyacrylates, polyethylene glycols, silicones, bentonites, talc, Silicic acid and zinc oxide or mixtures of these substances.

In addition to the active ingredient (s), sprays and powders can contain the usual carriers, for example lactose, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these. Sprays can additionally contain the usual blowing agents, for example chlorofluorocarbon.

In addition to the active ingredient (s), solutions and emulsions can include the usual carriers such as solvents, solubilizers and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils, in particular cottonseed oil, peanut oil, Contain cashew nut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, glycerin formal, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

For parenteral administration, the solutions and emulsions can also be in sterile and blood isotonic form.

In addition to the active ingredient (s), suspensions can contain the usual carriers such as liquid diluents, for example ethyl alcohol, propylene glycol, suspending agents, for example ethoxylated isosteayl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, Contain bentonite, agar-agar or tragacanth or mixtures of these substances.

The formulation forms mentioned can also contain colorants, preservatives and odor and taste-improving additives, for example peppermint oil and eucalyptus oil and sweeteners, for example saccharin.

The therapeutically active compounds should be present in the pharmaceutical preparations listed above preferably in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95% by mass of the total mixture.

In addition to the active substances according to the invention, the pharmaceutical preparations listed above can also contain further pharmaceutical active substances.

The pharmaceutical preparations listed above are prepared in a customary manner by known methods, for example by mixing the active compounds with the excipients.

The present invention also includes the use of the active compounds according to the invention and the pharmaceutical preparations which contain one or more active compounds in human and veterinary medicine to prevent, improve and / or cure the diseases mentioned above.

The active ingredients or the pharmaceutical preparations can be administered locally, orally, parenterally, rectally and / or as an aerosol, preferably parenterally.

In general, it has proven to be advantageous to administer the active ingredient (s) according to the invention in total amounts of about 0.1 to about 100, preferably 0.5 to 50 mg / kg of body weight per 24 hours, if appropriate in the form of several individual doses, in order to achieve the desired results .

However, it may be necessary to deviate from the doses mentioned, depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and administration of the drug, and the period or interval within which the administration takes place. In some cases it may be sufficient to make do with less than the amount of active ingredient mentioned above, while in other cases the amount of active ingredient mentioned above has to be exceeded.

The following examples illustrate the invention and are not intended to limit its scope in any way.

example 1 N, N'-1,3-propanedlylbis-D-gluconamide

7.13 g of D (+) - gluconic acid 1,5-lactone are dissolved in 40 ml of amine-free dimethylformamide, and 1.67 ml of 1,3-diaminopropane are added. Then heated to 60 C and stirred for 5 hours. The resulting precipitate is filtered off, washed with methanol and dried. 7.96 g of a white powder are obtained.

Example 2 N, N'-1,12-dodecanediylbis-D-gluconamide

7.1 g of D-gluconic acid 1,5-lactone are suspended in 90 ml of dimethylformamide, 4.0 g of 1,12-diaminododecane are added, and the mixture is stirred for 5 hours at 60 ° C. After cooling, the mixture is stirred in 0 3 l of methanol, collect the solid and wash it with methanol. Now the solid is suspended in 1N HCl, stirred for one hour at room temperature, the solid is collected again and washed with water, acetone and finally with diethyl ether. 9.9 g of a white powder are obtained.

Example 3 N, N'-1,3-propanediylbis [4-0-β-D-galactopyranosyl-D-gluconamide]

395.4 g of calcium lactobionate are dissolved in 1.2 l of water and the solution is treated for 1 hour with 0.7 l of Lewatit S 100 (H form) in a batch process. It is suctioned off and the exchanger is washed with 2 x 1 l of water. The combined eluates are largely concentrated in vacuo. Now the glassy residue is dissolved in 800 ml of amine-free dimethylformamide, 800 ml of n-hexane are added and the mixture is heated to boiling with vigorous stirring on a water separator. When the water separation has ended, the n-hexane is distilled off, 43 ml of 1,3-diaminopropane are added and the mixture is stirred at 63 ° C. for 7 hours. The mixture is then stirred into 5 l of isopropanol, the solid is collected and washed with 1 l of isopropanol. After drying, 350 g of a white solid are obtained. To clean it, dissolve it in 2 liters of water. The solution is treated for 1 hour with 100 ml Lewatit S 100 (H ⁺ form), then with 100 ml Amberlyst A 21 (OH form). After freeze-drying, the title compound is obtained in pure form.

Example 4 N, N'-1,6-hexanediylbis [4-O-β-D-galactopyranosyl-D-glyconamide]

17.0 g of lactobionic acid 1,5-lactone are suspended in 100 ml of amine-free dimethylformamide, 2.9 g of 1,6-diaminohexane are added, and the mixture is stirred at 80 ° C. for 6 hours. After cooling, the mixture is filtered and the filtrate is dissolved in 1 liter Diethyl ether stirred. The partially oily precipitate is dissolved in 50 ml of water and treated with 80 ml of ion exchanger (Merck 4765, H ⁺ form). It is filtered and, after lyophilization, 19.5 g of colorless powder is obtained, which decomposes at 175 ° C. with a brown color.

Example 5 N, N'-1,12-dodecanediylbis [4-O-β-D-galactopyranosyl-D-gluconamide]

40.8 g of lactobionic acid-1,5-lactone are suspended in 150 ml of amine-free dimethylformamide, 12.0 g of 1,12-diaminododecane are added, and the mixture is stirred at 60 ° C. for 6 hours. The mixture is added dropwise to 1.5 l of isopropanol with stirring . The precipitate is washed with isopropanol and dissolved in 250 ml of water. The solution is first treated with 20 ml of an acidic ion exchanger (Lewatit S 100), then with a basic ion exchanger (Merck 4767). After lyophilization, 35.0 g of a colorless powder are obtained. Melting point: 79 - 81 ° C

Example 6 N, N'-1,9-nonandiylbis [4-0-ß-D-galactopyranosyl-D-glyconamide]

Preparation and purification as in Example 5. 15.0 g of the title compound are obtained from 15.0 g of lactobionic acid 1,5-lactone and 3.47 g of 1,9-diaminononane.

Example 7 N, N'-1,12-dodecanediylbis (4-O-β-D-glucopyranosyl-D-gluconamide)

2.04 g of cellobionic acid 1,5-lactone (HW Diehl et al., Carbohydr. Res. 38, 364 (1974)) is reacted analogously to Example 5 with 0.60 g of 1,12-diaminododecane and 0.60 is obtained g of the title compound.

Example 8 N, N'-1,12-dodecanediylbis (4-O-α-D-glucopyranosyl-D-gluconamide)

20.0 g of calcium maltobionate (WN Emmerling, B. Pfannemüller, Starch 33, 202, (1981)) are reacted analogously to Example 3 with 1,12-di-aminododecane and 17.8 g of product are obtained.

Example 9 N, N'-1,12-dodecanediylbis (6-0-a-D-galactopyranosyl) -D-gluconamide)

3.96 g of potassium melibionate (Sigma-Chemie) are reacted analogously to Example 3 with 1.00 g of 1,12-diaminododecane, and 3.3 g of the title compound are obtained.

Example 10 N, N'-1,3-propanediylbis (6-0-a-D-galactopyranosyl-D-gluconamide)

Preparation analogous to Example 9. 3.06 g of product is obtained from 3.96 g of potassium melibionate and 0.37 g of 1,3-diaminopropane.

Example 11 N, N'-α, α'-m-xylene diyl bis [4-O-β-D-galactopyranosyl-D-gluconamide]

If 17.0 g of lactobionic acid 1,5-lactone and 3.3 ml of 3- (aminomethyl) benzylamine are used in a process according to Example 5, 12.2 g of the title compound are obtained in the same way as a colorless powder.

Example 12 N, N'-4,4'-dicycfohexyimethandiyibis [4-O-β-D-galactopyranosyl-D-gluconamide]

Preparation and purification analogous to Example 5 from 17.0 g lactobionic acid 1,5-lactone and 5.3 g 4,4'-diamino-dicyclohexylmethane. Yield: 21.3 g.

Example 13 N, N'-1,6- (3,4-dithiahexanediylbis) 4-O-β-D-galactopyranosyl-D-gluconamide

17.0 g of lactobionic acid 1,5-lactone and 5.63 g of cystamine dihydrochloride in 50 ml of amine-free DMF are mixed with 6.9 ml of triethylamine at room temperature and then stirred for 6 hours at 60 ° C. It is precipitated with 500 ml of ethanol and treated the precipitation as in Example 5. 13.2 g of white powder are obtained.

Example 14 N, N'-1,7- (4-azaheptanediylbis) 4-O-β-D-galactopyranosyl-D-giuconamide

17.0 g of lactobionic acid 1,5-lactone is suspended in 100 ml of amine-free dimethylformamide, 2.28 ml of bis (3-aminopropyl) amine are added at room temperature and the mixture is stirred for 10 hours. Then stirred for 4 hours at 40 C and filtered. The filtrate is stirred into 900 ml of acetone and, after washing with acetone and drying, 23.0 g of white crystals are obtained. These are dissolved in 80 ml of water and precipitated with 900 ml of acetone. The partly oily precipitate is dissolved in 150 ml of water, filtered and lyophilized. Yield: 16.5 g.

Example 15 N, N'-1,12- (4,9-dioxadodecanediylbis) 4-O-β-D-galactopyranosyl-D-gluconamide

Preparation and purification as in Example 5. 18.9 g of the title compound are obtained from 17.0 g of lactobionic acid 1,5-lactone and 5.1 g of 1,12-diamino-4,9-dioxadodecane.

Example 16 N, N'-dimethyl-N, N'-1,2-ethanediylbis (4-0-ß-D-galactopyranosyl-D-gluconamide)

Preparation and purification analogous to Example 5. 3.0 g of the title compound are obtained from 3.40 g of lactobionic acid 1,5-lactone and 0.44 g of N, N'-dimethylethylenediamine.

Example 17 N, N'-1,5- (1-ethoxycarbonyl) pentanediylbis (4-0-ß-D-galactopyranosyl-D-gluconamide

2.47 g of lysine ethyl ester dihydrochloride are suspended in 40 ml of amine-free dimethylformamide, 3.0 ml of triethylamine are added and the mixture is stirred for 15 minutes. Then 6.8 g of lactobionic acid-1,5-lactone are added, the mixture is warmed to 60 ° C. and stirred for 1 day. It is filtered and the filtrate is stirred into 400 ml of isopropanol. The precipitate is collected, dissolved in 60 ml of dimethylformamide and precipitated again with 300 ml of isopropanol. The precipitation is repeated, washed with isopropanol and diethyl ether, and 4.05 g of a white powder is thus obtained.

Example 18 Decasodium N, N'-1,3-propanediylbis (2,3,4,5,6-penta-0-sulfo-D-gluconamide)

4.30 g of N, N'-1,3-propanediylbis-D-gluconamide are suspended in 50 ml of dry dimethylformamide, heated to 40 ° C. and mixed with 23.9 g of pyridine-sulfur trioxide complex with stirring. After a few minutes, the product in the form of the pyridinium salt precipitates as an oil. After 1 hour, the mixture is allowed to cool and the supernatant solution is decanted off. The oil is dissolved in 50 ml of water and brought to pH = 10 with 6 N sodium hydroxide solution. The solution is made up to 90 ml with water and stirred into 350 ml of a 1% sodium acetate solution. The precipitate is washed with methanol and dried. 18.6 g of a colorless powder are obtained. This is dissolved in 186 ml of water. 227 ml of methanol are stirred into the solution and left to stand for 15 hours. Decant from the separated oil and rub it with methanol. The precipitation is repeated until the title compound is pure. Decomposition from 190 ° C with brown coloring.

Example 19 Decasodium N, N'-1,12-dodecanediylbis (2,3,4,5,6-penta-D-sulfo-D-gluconamide)

5.60 g of N, N'-1,12-dodecanediylbis-D-gluconamide are reacted analogously to Example 18 with 25.5 g of pyridine-sulfur trioxide complex, and 20.5 g of crude product are obtained. The pure product is obtained by gel chromatography of an aqueous solution on a Sephadex G 25 column. After freeze-drying, a colorless powder is obtained which decomposes between 175 ° C and 189 ° C with a brown color.

Example 20 Hexadecasodium N, N'-1,3-propanediylbis [2,3,5,6-tetra-O-sulfo-4-O- (2,3,4,6-tetra-O-sulfo, 9-D- galactopyranosyl) -D-gluconamide]

79.1 g of calcium lactobionate are dissolved in 240 ml of water and the solution is treated with 240 ml of Lewatit S 100 (H form). The ion exchanger is washed with 3 x 200 ml of water and the combined solutions are concentrated as much as possible. The glassy residue is dissolved in 700 ml of amine-free dimethylformamide and heated to boiling with 600 ml of n-hexane on a water separator. When the water separation has ended, the n-hexane is evaporated off and 7.7 g of 1,3-diaminopropane in 50 ml of dimethylformamide are added to the solution at room temperature. After stirring for 5 hours at 60 ° C., the mixture is allowed to cool to about 30 ° C., diluted with 450 ml of dimethylformamide and 400 g of pyridine-sulfur trioxide complex are added in portions with stirring. The mixture is stirred between 40 and 45 ° C for 1 hour and allowed to cool. It is decanted from the separated oil, this is dissolved in 500 ml of water and the solution is adjusted to pH = 10 with 30% sodium hydroxide solution. it is supplemented with water to a volume of 1.5 l and the solution is stirred into 4.5 l of a 1% methanolic sodium acetate solution. The precipitate is stirred with 1 l of methanol, suction filtered and dried. 250 g of a yellowish powder are obtained. This is dissolved in 2 l of water, mixed with 250 ml of 30% hydrogen peroxide and stirred for 1 hour at 45 C. After cooling, the mixture is neutralized and made up to 2.5 l with water. The solution is stirred into 3.06 l of methanol and let stand for 15 hours. Man decants from separated oil and rubs it with methanol. After drying, 188.5 g of colorless powder are obtained. the precipitation process is repeated four times and finally about 50 g of the pure title compound is obtained as a colorless powder which turns brown from 172 ° C. with decomposition and does not melt below 250 ° C.

Example 21 Pentadecasodium pentadeca-O-sulfo-N, N'-1,3-propaniylbis (4-O-β-D-galactopyranosyl-D-gluconamide)

3.77 g of N, N'-1,3-propanediylbis (4-0-β-D-galactopryanosyl-D-gluconamide) are dissolved in 60 ml of dry dimethylformamide, and 13.5 g are added in portions at 40 ° C. with stirring Pyridine-sulfur trioxide complex. After 1 hour, the mixture is worked up as in Example 18 and 10.3 g of yellowish, sulfate-containing crude product are obtained. It is dissolved in 90 ml of water, mixed with 10 ml of 30% hydrogen peroxide and stirred for 1 hour at 45 ° C. After cooling, 230 ml of methanol are stirred in and the mixture is left to stand for 15 hours. It is decanted from the separated oil, this is triturated with methanol and 6.72 g of sulfate-free product (with a sulfur content of 20.6%) are obtained. It is dissolved in 67 ml of water, 82 ml of methanol are stirred in and the mixture is left to stand for 15 hours. It is decanted from the separated oil and a further 74 ml of methanol are stirred into the supernatant. After 15 hours, the oil is isolated and the fractional precipitation is repeated several times as above until the title compound is pure. 0.53 g of colorless powder is obtained, which decomposes at 180 C with a brown color.

Example 22 Hexadecamorpholinium N, N'-1,3-propanediylbis [2,3,5,6-tetra-O-su) fo-4-O- (2,3,4,6-tetra-O-sulfo-, 6- D-gatactopy-ranosyl) -D-gluconamide]

A solution of 1.76 g of the sodium salt from Example 20 is treated for 15 minutes with 16 ml of Lewatit S-100 (H form), the ion exchanger is filtered off and 1.03 g of morpholine are added to the filtrate. After lyophilization, 2.40 g of yellowish powder is obtained. Decomposition from 120 ° C and blackening at 210 ° C

Example 23 Hexadecasodium N, N'-1,6-hexanediylbis [2,3,5,6-tetra-O-sulfo-4-O- (2,3,4,6-tetra-O-sulfo-β-D-galactopyranosyl ) -D-gluconamide]

16.3 g of N, N'-1,6-hexanediylbis (4-O-β-D-galactopyranosyl-D-gluconamide) are reacted with 75.0 g of pyridine-sulfur trioxide complex analogously to Example 18. After the first precipitation, 56.9 g of a yellowish powder are obtained, which is cleaned as in Example 20. About 15 g of the pure title compound are finally obtained in the form of a colorless powder which sinters at 120 ° C. Decomposition from 170 ° C with brown coloring.

Example 24 Hexadecasodium N, N'-1,9-nonandiylbis [2,3; 5,6-tetra-O-suifo-4-O- (2,3,4,6-tetra-O-sulfo-β-D-galactopyranosyl ) -D-gluconamide]

Preparation and purification as in Example 23. 45.0 are obtained from 15.0 g of N, N'-1,9-nonanediylbis (4-O-β-D-galactopyranosyl-D-gluconamide) and 63.0 g of pyridine-sulfur trioxide complex .0 g of crude product. After cleaning: 10.5 g of colorless powder. Decomposition between 192-210 C with brown coloring

Example 25 Hexadecasodium N, N'-1,12-dodecanediylbis [2,3,5,6-tetra-O-sulfo-4-O- (2,3,4,6-tetra-O-sulfo, BD-galactopyranosyl) -D-gluconamide]

Preparation and purification as in Example 23. From 4.23 g of N, N'-1,12-dodecanediylbis (4-O-β-D-galactopyranosyl-D-gluconamide) and 19.1 g of pyridine-sulfur trioxide complex, 13 is obtained , 30 g of crude product. After cleaning: 3.5 g of pure title compound as a colorless powder. Decomposition between 188 - 198 ° C with brown coloring

Example 26 Hexadecasodium N, N'-1,12-dodecanediylbis [2,3,5,6-tetra-O-sulfo-4-O- (2,3,4,6-tetra-O-sulfo-β-D-glucopyranosyl ) -D-gluconamide]

From 0.34 g of N, N'-1,12-dodecanediylbis (4-0-β-D-glucopyranosyl-D-gluconamide) and 1.12 g of pyridine-sulfur trioxide complex, 0.68 g of crude is obtained analogously to Example 23 or 0.10 g of pure product. Decomposition from 148 ° C to 159 ° C with a brown color.

Example 27 Hexadecasodium N, N'-1,12-dodecanediylbis [2,3,5,6-tetra-O-suffo-4-O- (2,3,4,6-tetra-O-sulfo-α-D-glucopyranosyl ) -D-gluconamide]

From 12.8 g of N, N'-1,12-dodecanediylbis (4-0-aD-glucopyranosyl-D-gluconamide) and 64.6 g of pyridine-sulfur trioxide complex, 47.5 g of crude or 3.0 g of pure product. Decomposition from 175 ° C to 189 ° C with brown coloring.

Example 28 Hexadecasodium N, N'-1,12-dodecanediylbis [2,3,4,5-tetra-O-sulfo-6-O- (2,3,4,6-tetra-O-sulfo-α-D-galactopyranosyl ) -D-gluconamide]

Analogously to Example 23, 3.30 g of N, N'-1,12-dodecanediylbis (6-O-α-D-galactopyranosyl-D-gluconamide) and 14.9 g of pyridine-sulfur trioxide complex give 9.7 g of crude or 3.4 g of pure product that sinters at 57 ° C. Decomposition from 182 ° C with brown coloring.

Example 29 Hexadecasodium N, N'-1,3-propanediylbis [2,3,4,5-tetra-O-sulfo-6-O- (2,3,4; 6-tetra-O-sulfo-α-D-galactopyranosyl ) -D-gluconamide]

From 0.34 g of N, N'-1,3-propanediylbis (6-O-α-D-galactopyranosyl-D-gluconamide) and 2.0 g of pyridine-sulfur trioxide complex, 0.96 g of crude is obtained analogously to Example 23 or 0.50 g of pure product. Decomposition from 168 ° C with a brown color

Example 30 Hexadecasodium N, N'-α, α-m-xylene diylbis [2,3,5,6-tetra-O-sulfo-4-O- (2,3,4,6-tetra-O-sulfo-β-D -galactopyranosyl) -D-gluconamide]

12.0 g of N, N'-α, α'-m-xylenediylbis (4-O-β-D-galactopyranosyl-D-gluconamide) and 58.8 g of pyridine-sulfur trioxide complex are obtained analogously to Example 23 28, 0 g raw or 5.3 g pure product. Decomposition from 157 ° C with brown coloring.

Example 31 Hexadecasodium N, N'-4,4-dicyclohexylmethanediylbis [2,3,5,6-tetra-O-sulfo-4-O- (2,3,4,6-tetra-O-sulfo-β-D-galactopyranosyl ) -D-gluconamide]

Analogously to Example 23, 70.7 g is obtained from 25.7 g of N, N'-4,4'-dicyclohexylmethanediylbis (4-O-β-D-galactopyranosyl-D-gluconamide) and 114.7 g of pyridine-sulfur trioxide complex raw or 15.2 g pure product that sinters from 120 ° C. Decomposition from 180 ° C with brown coloring.

Example 32 Hexadecasodium N, N'-1,6- (3,4-dithiahexanediylbis) [2,3,5,6-tetra-O-sulfo-4-O- (2,3,4,6-tetra-O-sulfo -β-D-gaiac-topyranosyl) -D-gluconamide]

From 11.2 g of N, N'-1,6- (3,4-dithiahexanediylbis) 4-0-β-D-gaiactopyranosyl-D-gluconamide) and 53.4 g of pyridine-sulfur trioxide complex are obtained analogously to Example 23 38.0 g of tube and 8.5 g of pure product. Decomposition from 163 ° C with a brown color.

Example 33 Hexadecasodium N, N'-1,7- (4-azaheptanediylbis) [2,3,5,6-tetra-O-sulfo-4-O- (2,3,4,6-tetra-O-sulfo-β -D-galactopyranosyl) -D-gluconamide]

From 11.0 g of N, N'-1,7- (4-azaheptanediylbis) 4-O-β-D-galactopyranosyl-D-gluconamide and 50.0 g of pyridine-sulfur trioxide complex are obtained analogously to Example 23 15.4 g raw and 2.2 g pure product. Decomposition from 165 ° C with a brown color.

Example 34 Hexadecasodium N, N'-1,12- (4,9-dioxadodecanediylbis) [2,3,5,6-tetra-O-sulfo-4-O- (2,3,4,6-tetra-O-sulfo -β-D-galactopyranosyl) -D-gluconamide]

According to Example 23, 37.2 are obtained from 18.2 g of N, N'-1,12- (4,9-dioxadodecanediylbis) 4-O-β-D-galactopyranosyl-D-gluconamide and 59.0 g of pyridine-sulfur trioxide complex , 1 g raw and 9.3 g pure product, which sinters from 120 ° C. Decomposition from 170 ° C with brown coloring.

Example 35 Hexadecasodium N, N'-dimethyl-N, N'-1,2-ethanediylbis (2,3,5,6-tetra-O-sulfo-4-O- (2,3,4,6-tetra-O- sulfo-1β-D-galactopyranosyl) -D-gluconamide]

2.50 g of N, N'-dimethyl-N, N'-1,2-ethanediylbis (4-0-β-D-galactopyranosyl-D-gluconamide) and 12.4 g of pyridine-sulfur trioxide complex are obtained analogously Example 23 8.2 g of crude and 1.2 g of pure product. Decomposition at 188 - 200 ° C with brown coloring.

Example 36 Hexadecasodium N, N'-1,5- (1-ethoxycarbonyl) pentanediylbis [2,3,5,6-tetra-O-sulfo-4-O- (2,3,4,6-tetra-O-sulfo -β-D-galactopyranosyl) -D-gluconamide]

From 3.6 g of N, N'-1,5- (1-ethoxycarbonyl) pentanediylbis (4-O-β-D-galactopyranosyl-D-gluconamide) and 15.8 g of pyridine-sulfur trioxide complex is obtained according to Example 23 8.7 g raw and 1.2 g pure product that sinters from 60 ° C. Decomposition from 161 ° C with a brown color.

Example 37 N, N'-1,3-propanediylbis-D-gulonamide

3.56 g of D-gulono-γ-lactone and 0.84 ml of 1,3-diaminopropane are dissolved in 40 ml of dimethylformamide and the mixture is stirred at 60 ° C. for 6 hours. The mixture is then stirred into 200 ml of isopropanol and the precipitate is washed with Isopropanol and diethyl ether. The solid is dissolved in 20 ml of dimethylformamide and again precipitated with 200 ml of isopropanol. The precipitate is dissolved in water and freeze-dried. 2.2 g of a colorless powder are obtained.

Example 38 N, N'-1,2-propanediylbis-D-gaiactonamide

Analogously to Example 37, 4.1 g of the title compound is obtained as a colorless powder from 7.12 g of D-galactono-γ-lactone and 1.48 g of 1,2-diaminopropane.

Example 39 N, N'-1,4-butanediylbis-L-mannonamide

Analogously to Example 18, 2.4 g of the title compound are obtained as a colorless powder from 3.56 g of L-mannono-y-lactone and 0.90 g of putrescine. Decomposition from 181 - 188 ° C with brown coloring

Example 40 N, N'-dilactobionoyl hydrazine

Analogously to Example 37, 6.1 g of crude product are obtained from 6.8 g of lactobionic acid 1,5-lactone and 0.5 ml of hydrazine hydrate. Column chromatography on Fractogel TSK HW 40S provides the pure product as a colorless powder after freeze-drying.

Example 41 Decasodium N, N'-1,3-propanediylbis (2,3,4,5,6-penta-0-sulfo-D-gulonamide)

Analogously to Example 18, 2.2 g of N, N'-1,3-propanediylbis-D-gulonamide and 12.3 g of pyridine-sulfur trioxide complex give 9.8 g of crude or 6.4 g of pure product as a colorless powder . Decomposition below 185 ° C. Brown color.

Example 42 Decasodium N, N'-1,2-propanediylbis (2,3,4,5,6-penta-0-sulfo-D-galactonamide)

Analogously to Example 18, 13.0 g of crude or 9.8 g of pure product are obtained as a colorless powder from 3.3 g of N, N'-1,2-propanediylbis-D-galactonamide and 19.5 g of pyridine-sulfur trioxide complex . Decomposition from 191 ° C with brown coloring.

Example 43 Decasodium N, N'-1,4-butanediylbis (2,3,4,5,6-penta-0-sulfo-L-mannonamide)

Analogously to Example 18, 2.5 g of N, N'-1,4-butanediylbis-L-mannonamide and 14.1 g of pyridine-sulfur trioxide complex give 10.5 g of crude or 7.2 g of pure product as a colorless powder . Decomposition from 180 ° C with brown coloring

Example 44 Hexadecasodium N, N'-bis [2,3,5,6-tetra-O-sulfo-4-O- (2,3,4,6-tetra-O-sulfo, 8-D-galactopyranosyl) gluconoyl ] hydrazine

Analogously to Example 18, 17.5 g of crude or 7.3 g of pure product are obtained from 6.0 g of N, N'-dilactobionoylhydrazine and 33.7 g of pyridine-sulfur trioxide complex.

Example 45

5,000 kg of dry substance of hexadecasodium N, N'-1,3-propanediylbis [2,3,5,6-tetra-O-sulfo-4-O- (2,3,4,6-tetra-O -sulfo-β-D-galactopyranosyl) -D-gluconamide] with stirring in 40 l aqua ad iniectabilia. After the pH of the solution has been adjusted to 7.5 with dilute sodium hydroxide solution, the solution is made up to 50.00 l with aqua ad iniectabilia and filtered through a membrane filter with a pore size of 0.2 μm. The solution is filtered off under aseptic conditions in ampoules of 1 ml and these are melted off.

Claims (14)

1. Poly sulfuric acid esters of bis-aldonic acid amides and their derivatives of the general formula I

wherein either all radicals R ^I , R ² and R ³ independently of one another represent X, or two of the radicals R ¹ , R ² and R ^{3 represent} X, and the third represent a radical of the formulas II-VII,

X in the formulas I to VII simultaneously or independently of one another represents a hydrogen atom or the group -SO ₃ H, where at least one X represents the group -SO ₃ H, m stands for 0,1,2,3,4,5 or 6, A in formula I represents a straight-chain or branched, saturated alkylene radical having 2 to 22 carbon atoms which is optionally substituted by one or more -C0 ₂ R ⁵ radicals, and this alkylene radical optionally by up to 5 -O-, -S-, -SS- , -S (O) _n -, - -NH or / and -NR ⁶ groups or cycloalkylene or arylene radicals is interrupted, or A for a simple bond or the rest

stands, n is 1 or 2, R ⁴ , R ⁵ and R ⁶ mean simultaneously or independently of one another a hydrogen atom or a C ₁ -C ₆ alkyl radical, and their salts with inorganic or organic bases. 2. Compounds according to claim 1, characterized in that each X in the formulas I to VII represents the group -SO ₃ H. 3. Compounds according to claim 1, characterized in that in the formulas I to VII at least half of the groups X present is an -SO ₃ H group. 4. Compounds according to claim 1, characterized in that R ² and R ^{3 are} X. 5. Compounds according to claim 4, characterized in that R 'is the radical III or the radical VI with m = 0. 6. Compounds according to claim 1, characterized in that R ¹ and R ^{3 are} X. 7. Compounds according to claim 6, characterized in that R ² denotes the radical II or the radical VI with m = 0 or the radical VII with m = 0. 8. Compounds according to any one of claims 4 to 7, characterized in that A in formula I is a polymethylene radical - (CH ₂ ) _p with p = 2 to 22. 9. Compounds according to any one of claims 4 to 7, characterized in that A in formula I is a polymethylene radical - (CH2) p with p = 2 to 12. 10. Compounds according to any one of claims 4 to 7, characterized in that A in formula I represents a straight-chain alkylene radical having 2 to 22 carbon atoms, the chain of which is represented by the groups -O-, -S -, - SS-, -S (O ) _n -, O -C-NH- and / or -NR ^6- can be interrupted, where n and R ^{6 have} the meanings given in claim 1. 11. Compounds according to any one of claims 8 to 10, characterized in that A in formula I is substituted by one, two or more radicals -CO ₂ R ⁵ , where R ^{5 has} the meaning given in claim 1. 12. A process for the preparation of polysulfuric acid esters of bis-aldonic acid amides and their derivatives of the formula I according to claim 1, characterized in that bis-aldonic acid amides of the general formula IX,

wherein R ^I , R ² , R ³ , R ⁴ and A, which have the meanings given in claim 1, but where X in the formulas II to VII represents a hydrogen atom, in an aprotic solvent with a sulfating agent and the products thus obtained optionally with an inorganic or organic base converted into the corresponding salts. 13. The method according to claim 12, characterized in that in each case, without isolation of intermediates, aldonic acids of the general formula VIII,

wherein R ¹ , R ² and R ^{3 have} the meanings given in claim 1, but X in the formulas II to VII represents a hydrogen atom, converted into the bis-aldonic acid amides of the general formula IX and converted to their poly-sulfuric acid esters. 14. Medicament containing one or more compounds of general formula I, according to one of claims 1 to 11, together with conventional carriers and auxiliaries.